Product Survey: Automated liquid handlers and dispensers

by Harald Zähringer, Labtimes 06/2017

Traditional liquid handling robots are very versatile instruments, covering a wide volume range. But sometimes, it is wiser to switch beforehand to automated dispensers, capable of dispensing tiny nanolitre droplets.

Pipetting is the most essential task in a life science lab that nobody can escape. Though it is basically an easy job that may literally be run by robots, it is also very demanding and may ruin every experiment, if not done properly. What makes pipetting especially hard, is its repetitive nature, which not only stresses the thumb but is also mentally exhausting – keeping the concentration high during a tedious pipetting marathon can be a very tough experience.

No wonder then that many technicians, PhD students or postdocs, especially in wet labs, dream of pipetting robots aka automated liquid handlers and dispensers that take over their daily pipetting routine. Supposing their group leader’s pockets are not too empty, they may choose from a variety of commercial liquid handling robots, ranging from small benchtop budget models to full-blown workstations with “slightly” bigger footprints.

Liquid handlers are rather simple constructed instruments, built of three main parts: a deck, holding standardised microplates or other reaction vessels and containers; a liquid handling arm, installed above the deck, that slides back and forth along the x- and y-axes; and a pipetting head, orthogonally joined to the arm, that moves up and down the z-axis. This very basic setup is usually found in affordable, stripped down liquid handlers, intended for simple standard liquid handling tasks, such as serial dilutions.

Modular platforms

If you wish to do more, modular platforms expandable with additional robot arms, adapters, carriers for standard labware, barcode-reading modules and exchangeable pipetting heads with single or multichannel tips may be a good choice. But the higher flexibility comes at a higher price and, pretty soon, you end up at very complex instruments that usually need expert knowledge for programming.

Similar to manual or electronic pipettes, pipetting heads of liquid handlers function as air displacement or direct displacement pipettes. In the former case, tip content and piston are separated by a moveable air cushion that aspires the liquid into the tip or pushes it out. Direct displacement heads usually apply disposable syringes that get in direct contact with the pipetted liquid. Both types of heads can handle small microlitre volumes very efficiently and reliably. But they will get in big trouble at lower nanolitre volumes that disobey classical physical laws of liquids and follow the sometimes obscure rules of microfluidics instead.

Transferring tiny nanolitre volumes falls into the realm of automated dispensers, based on contact or non-contact dispensing techniques. In simple contact dispensers, a liquid drop is transferred via a thin pen. The pen is loaded with a defined volume by dipping it into a liquid reservoir. The liquid drop then sticks to the tip by adhesion forces and is deposited on the surface of the reaction vessel when the tip smoothly touches it. It is pretty obvious that the touchdown of the pen on the surface is very critical to the liquid transfer: slightly too hard and the surface or the pen are gone, slightly too soft and parts of the liquid drop will remain stuck to the pen.

To circumvent these problems, engineers designed non-contact dispensers based on piezoelectric, solenoid or acoustic dispensing. Especially acoustic dispensers have gained considerable interest in the last years. The physical principles of acoustic dispensing have been known for decades: liquid drops are ejected from the surface of a liquid, if high-energy acoustic waves are directed against the liquid.

But engineers struggled for years, to find a way of adjusting and focussing the energy of the acoustic waves, to obtain drops, with exactly defined size and volume. Once they had fixed this problem, the doors were open for today’s acoustic dispensers, working “inverse” to traditional liquid handlers: the drops are ejected from a reservoir into the wells of a receiving microplate, placed upside-down above the reservoir.

Acoustic dispensing stirred up quite a fuss in the drug-screening community, when researchers from British pharma ­giant AstraZeneca reported in 2010 about discrepancies in drug potency data (IC50 values) obtained after adjusting drug concentrations, either by direct dilution, applying an acoustic dispenser, or serial dilution with a conventional liquid handler. The researchers found considerably lower IC50 values (higher affinity values, respectively), for all tested drugs after direct dilution with the acoustic dispenser.

Disturbing results

Inspired by the AstraZeneca report, a group led by Sean Ekins, then working for Collaborations in Chemistry, computed pharmacophores, i.e., computer-generated interactions of macromolecules with ligands, based on IC50 values, and analysed whether different dilution techniques had an impact on the modelling (PLoS ONE 8(5): e62325).

The results were even more disturbing. According to Ekins et al., pharmacophores calculated after serial dilution with a liquid handler were not viable, in contrast to pharmacophores generated after direct dilution with an acoustic dispenser.

To get a deeper understanding of this dilution conundrum, Ekins joined forces with drug designer John Chodera from the Memorial Sloan Kettering Institute, USA. To cut a long story short, Ekins and Chodera are pretty sure that the serial dilution of small volumes with fixed washable tips and a liquid handler leads to a significant accumulation of bias, even after a short (8-point) dilution series (Journal of Computer-Aided Molecular Design, 29, 12, 1073-86). Though Ekins and Chodera speculate that the adsorption of liquids to the plastic surface of the tips may be responsible for the error during serial dilution, the exact reason is still not clear. But whatever it is, AstraZeneca has taken action and completely switched to acoustic dispensing in its drug discovery facilities.

First published in Labtimes 06/2017. We give no guarantee and assume no liability for article and PDF-download.

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